Locally Injectable, ROS-Scavenging, and ROS-/pH-Responsive Polymeric-Micelles-Embedded Hydrogels for Precise Minimally Invasive and Long-Lasting Rheumatoid Therapy.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitis, bone-erosion, and joint-destruction. Here, we developed a locally injectable, ROS-scavenging, and ROS-/pH-responsive drug-delivery platform (HC@PTM) by bio-compositing of aldolizing hyaluronic acid (HA) crosslinked with chitosan (CS), and ROS-triggered/eliminated micelles (PTM) coupled with the drug methotrexate(MTX). The PTM efficiently eradicate excessive ROS in RA-joints, precisely triggering drug-release within inflamed arthritic-sites and further confer exceptional antioxidant origins to HC@PTM. HC@PTM with outstanding shape-adaptability and self-repairing properties effectively conformed to irregular articular cartilage while resisting joint-induced deformations. Further, the platform's pH-responsive nature enables on-demand drug-release within acidic inflamed synovium, serving as a drug-reservoir for precise and sustained therapeutic effects. Extensive in vitro and in vivo investigations confirm HC@PTM's ability to induce M2 macrophage polarization, downregulate inflammatory factor expression, and ameliorate the RA-microenvironment, ultimately achieving synergistic therapeutic outcomes. This study represents significant advancements in precise and long-term RA-treatment through a minimally invasive approach, offering potential strategies for novel precision medicine.